Anemia

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Anemia
Classification and external resources ICD-10 ICD-9 DiseasesDB MedlinePlus eMedicine MeSH D50-D64 280-285 663 000560 med/132 emerg/808 emerg/734 D000740

Anemia (/nimi/; also spelled anaemia and anmia; from Greek anaimia, meaning lack of blood) is a decrease in number of red blood cells (RBCs) or less than the normal quantity of hemoglobin in the blood.[1][2] However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin deficiency. Because hemoglobin (found inside RBCs) normally carries oxygen from the lungs to the tissues, anemia leads to hypoxia (lack of oxygen) in organs. Since all human cells depend on oxygen for survival, varying degrees of anemia can have a wide range of clinical consequences. Anemia is the most common disorder of the blood. There are several kinds of anemia, produced by a variety of underlying causes. Anemia can be classified in a variety of ways, based on the morphology of RBCs, underlying etiologic mechanisms, and discernible clinical spectra, to mention a few. The three main classes of anemia include excessive blood loss (acutely such as a hemorrhage or chronically through low-volume loss), excessive blood cell destruction (hemolysis) or deficient red blood cell production (ineffective hematopoiesis). There are two major approaches: the "kinetic" approach which involves evaluating production, destruction and loss,[3] and the "morphologic" approach which groups anemia by red blood cell size. The morphologic approach uses a quickly available and low cost lab test as its starting point (the MCV). On the other hand, focusing early on the question of production may allow the clinician to expose cases more rapidly where multiple causes of anemia coexist.

Contents
[hide]

1 Signs and symptoms

2 Diagnosis 3 Classification o 3.1 Production vs. destruction or loss o 3.2 Red blood cell size o 3.3 Hyperanemia o 3.4 Refractory anemia o 3.5 Grading of anemia 4 Causes o 4.1 Impaired production o 4.2 Increased destruction o 4.3 Blood loss o 4.4 Fluid overload 5 Treatments o 5.1 Blood transfusions o 5.2 Hyperbaric oxygen 6 References 7 External links

[edit] Signs and symptoms

Main symptoms that may appear in anemia.[4] Anemia goes undetermined in many people, and symptoms can be minor or vague. The signs and symptoms can be related to the anemia itself, or the underlying cause. Most commonly, people with anemia report non-specific symptoms of a feeling of weakness, or fatigue, general malaise and sometimes poor concentration. They may also report dyspnea (shortness of breath) on exertion. In very severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing cardiac output. The patient may have symptoms related to this, such as palpitations, angina (if preexisting heart disease is present), intermittent claudication of the legs, and symptoms of heart failure.

On examination, the signs exhibited may include pallor (pale skin, mucosal linings and nail beds) but this is not a reliable sign. There may be signs of specific causes of anemia, e.g., koilonychia (in iron deficiency), jaundice (when anemia results from abnormal break down of red blood cells in hemolytic anemia), bone deformities (found in thalassemia major) or leg ulcers (seen in sickle-cell disease). In severe anemia, there may be signs of a hyperdynamic circulation: tachycardia (a fast heart rate), bounding pulse, flow murmurs, and cardiac ventricular hypertrophy (enlargement). There may be signs of heart failure. Pica, the consumption of non-food based items such as dirt, paper, wax, grass, ice, and hair, may be a symptom of iron deficiency, although it occurs often in those who have normal levels of hemoglobin. Chronic anemia may result in behavioral disturbances in children as a direct result of impaired neurological development in infants, and reduced scholastic performance in children of school age. Restless legs syndrome is more common in those with iron-deficiency anemia. Less common symptoms may include swelling of the legs or arms, chronic heartburn, vague bruises, vomiting, increased sweating, and blood in stool.

[edit] Diagnosis

Peripheral blood smear microscopy of a patient with iron-deficiency anemia. Anemia is typically diagnosed on a complete blood count. Apart from reporting the number of red blood cells and the hemoglobin level, the automatic counters also measure the size of the red blood cells by flow cytometry, which is an important tool in distinguishing between the causes of anemia. Examination of a stained blood smear using a microscope can also be helpful, and is sometimes a necessity in regions of the world where automated analysis is less accessible. In modern counters, four parameters (RBC count, hemoglobin concentration, MCV and RDW) are measured, allowing others (hematocrit, MCH and MCHC) to be calculated, and compared to values adjusted for age and sex. Some counters estimate hematocrit from direct measurements.

WHO's Hemoglobin thresholds used to define anemia[5] (1 g/dL = 0.6206 mmol/L) Age or gender group Hb threshold (g/dl) Hb threshold (mmol/l) Children (0.55.0 yrs) 11.0 6.8 Children (512 yrs) 11.5 7.1 Teens (1215 yrs) 12.0 7.4 Women, non-pregnant (>15yrs) 12.0 7.4 Women, pregnant 11.0 6.8 Men (>15yrs) 13.0 8.1 Reticulocyte counts, and the "kinetic" approach to anemia, have become more common than in the past in the large medical centers of the United States and some other wealthy nations, in part because some automatic counters now have the capacity to include reticulocyte counts. A reticulocyte count is a quantitative measure of the bone marrow's production of new red blood cells. The reticulocyte production index is a calculation of the ratio between the level of anemia and the extent to which the reticulocyte count has risen in response. If the degree of anemia is significant, even a "normal" reticulocyte count actually may reflect an inadequate response. If an automated count is not available, a reticulocyte count can be done manually following special staining of the blood film. In manual examination, activity of the bone marrow can also be gauged qualitatively by subtle changes in the numbers and the morphology of young RBCs by examination under a microscope. Newly formed RBCs are usually slightly larger than older RBCs and show polychromasia. Even where the source of blood loss is obvious, evaluation of erythropoiesis can help assess whether the bone marrow will be able to compensate for the loss, and at what rate. When the cause is not obvious, clinicians use other tests: ESR, ferritin, serum iron, transferrin, RBC folate level, serum vitamin B12, hemoglobin electrophoresis, renal function tests (e.g. serum creatinine). When the diagnosis remains difficult, a bone marrow examination allows direct examination of the precursors to red cells.

[edit] Classification
[edit] Production vs. destruction or loss
The "kinetic" approach to anemia yields what many argue is the most clinically relevant classification of anemia. This classification depends on evaluation of several hematological parameters, particularly the blood reticulocyte (precursor of mature RBCs) count. This then yields the classification of defects by decreased RBC production versus increased RBC destruction and/or loss. Clinical signs of loss or destruction include abnormal peripheral blood smear with signs of hemolysis; elevated LDH suggesting cell destruction; or clinical signs of bleeding, such as guaiac-positive stool, radiographic findings, or frank bleeding.

The following is a simplified schematic of this approach: Anemia Reticulocyte production index shows inadequate production response to anemia. No clinical findings consistent with hemolysis or blood loss: pure disorder of production. Macrocytic anemia (MCV>100) Clinical findings and abnormal MCV: hemolysis or loss and chronic disorder of production*. Normocytic anemia (80<MCV<100) Reticulocyte production index shows appropriate response to anemia = ongoing hemolysis or blood loss without RBC production problem. Clinical findings and normal MCV= acute hemolysis or loss without adequate time for bone marrow production to compensate**. Microcytic anemia (MCV<80)

* For instance, sickle cell anemia with superimposed iron deficiency; chronic gastric bleeding with B12 and folate deficiency; and other instances of anemia with more than one cause. ** Confirm by repeating reticulocyte count: ongoing combination of low reticulocyte production index, normal MCV and hemolysis or loss may be seen in bone marrow failure or anemia of chronic disease, with superimposed or related hemolysis or blood loss.

[edit] Red blood cell size

In the morphological approach, anemia is classified by the size of red blood cells; this is either done automatically or on microscopic examination of a peripheral blood smear. The size is reflected in the mean corpuscular volume (MCV). If the cells are smaller than normal (under 80 fl), the anemia is said to be microcytic; if they are normal size (80100 fl), normocytic; and if they are larger than normal (over 100 fl), the anemia is classified as macrocytic. This scheme quickly exposes some of the most common causes of anemia; for instance, a microcytic anemia is often the result of iron deficiency. In clinical workup, the MCV will be one of the first pieces of information available; so even among clinicians who consider the "kinetic" approach more useful philosophically, morphology will remain an important element of classification and diagnosis. Here is a schematic representation of how to consider anemia with MCV as the starting point: Anemia Macrocytic anemia (MCV>100) Normocytic anemia (MCV 80100) Microcytic anemia (MCV<80)

reticulocyte count

reticulocyte count

Other characteristics visible on the peripheral smear may provide valuable clues about a more specific diagnosis; for example, abnormal white blood cells may point to a cause in the bone marrow. [edit] Microcytic Main article: Microcytic anemia Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which could be caused by several etiologies:

Heme synthesis defect o Iron deficiency anemia o Anemia of chronic disease (more commonly presenting as normocytic anemia) Globin synthesis defect o alpha-, and beta-thalassemia o HbE syndrome o HbC syndrome o and various other unstable hemoglobin diseases Sideroblastic defect o Hereditary sideroblastic anemia o Acquired sideroblastic anemia, including lead toxicity o Reversible sideroblastic anemia

Iron deficiency anemia is the most common type of anemia overall and it has many causes. RBCs often appear hypochromic (paler than usual) and microcytic (smaller than usual) when viewed with a microscope.

Iron deficiency anemia is caused by insufficient dietary intake or absorption of iron to replace losses from menstruation or losses due to diseases.[6] Iron is an essential part of hemoglobin, and low iron levels result in decreased incorporation of hemoglobin into red blood cells. In the United States, 20% of all women of childbearing age have iron deficiency anemia, compared with only 2% of adult men. The principal cause of iron deficiency anemia in premenopausal women is blood lost during menses. Studies have shown that iron deficiency without anemia causes poor school performance and lower IQ in teenage girls, although this may be due to socioeconomic factors.[7][8] Iron deficiency is the most prevalent deficiency state on a worldwide basis. Iron deficiency is sometimes the cause of abnormal fissuring of the angular (corner) sections of the lips (angular stomatitis). Iron deficiency anemia can also be due to bleeding lesions of the gastrointestinal tract. Fecal occult blood testing, upper endoscopy and lower endoscopy should be performed to

identify bleeding lesions. In men and post-menopausal women the chances are higher that bleeding from the gastrointestinal tract could be due to colon polyp or colorectal cancer. Worldwide, the most common cause of iron deficiency anemia is parasitic infestation (hookworm, amebiasis, schistosomiasis and whipworm).[9]

[edit] Macrocytic Main article: Macrocytic anemia

Megaloblastic anemia, the most common cause of macrocytic anemia, is due to a deficiency of either vitamin B12, folic acid (or both). Deficiency in folate and/or vitamin B12 can be due either to inadequate intake or insufficient absorption. Folate deficiency normally does not produce neurological symptoms, while B12 deficiency does. o Pernicious anemia is caused by a lack of intrinsic factor. Intrinsic factor is required to absorb vitamin B12 from food. A lack of intrinsic factor may arise from an autoimmune condition targeting the parietal cells (atrophic gastritis) that produce intrinsic factor or against intrinsic factor itself. These lead to poor absorption of vitamin B12. o Macrocytic anemia can also be caused by removal of the functional portion of the stomach, such as during gastric bypass surgery, leading to reduced vitamin B12/folate absorption. Therefore one must always be aware of anemia following this procedure. Hypothyroidism Alcoholism commonly causes a macrocytosis, although not specifically anemia. Other types of liver disease can also cause macrocytosis. Methotrexate, zidovudine, and other drugs that inhibit DNA replication.

Macrocytic anemia can be further divided into "megaloblastic anemia" or "non-megaloblastic macrocytic anemia". The cause of megaloblastic anemia is primarily a failure of DNA synthesis with preserved RNA synthesis, which result in restricted cell division of the progenitor cells. The megaloblastic anemias often present with neutrophil hypersegmentation (610 lobes). The nonmegaloblastic macrocytic anemias have different etiologies (i.e. there is unimpaired DNA globin synthesis,) which occur, for example in alcoholism. In addition to the non-specific symptoms of anemia, specific features of vitamin B12 deficiency include peripheral neuropathy and subacute combined degeneration of the cord with resulting balance difficulties from posterior column spinal cord pathology.[10] Other features may include a smooth, red tongue and glossitis. The treatment for vitamin B12-deficient anemia was first devised by William Murphy who bled dogs to make them anemic and then fed them various substances to see what (if anything) would make them healthy again. He discovered that ingesting large amounts of liver seemed to cure the disease. George Minot and George Whipple then set about to isolate the curative substance chemically and ultimately were able to isolate the vitamin B12 from the liver. All three shared the 1934 Nobel Prize in Medicine.[11]

[edit] Normocytic Main article: Normocytic anemia Normocytic anemia occurs when the overall hemoglobin levels are decreased, but the red blood cell size (mean corpuscular volume) remains normal. Causes include:

Acute blood loss Anemia of chronic disease Aplastic anemia (bone marrow failure) Hemolytic anemia

[edit] Dimorphic When two or more causes of anemia act simultaneously, e.g., macrocytic hypochromic, due to hookworm infestation leading to deficiency of both iron and vitamin B12 or folic acid [12] or following a blood transfusion more than one abnormality of red cell indices may be seen. Evidence for multiple causes appears with an elevated RBC distribution width (RDW), which suggests a wider-than-normal range of red cell sizes. [edit] Heinz body anemia Heinz bodies form in the cytoplasm of RBCs and appear like small dark dots under the microscope. There are many causes of Heinz body anemia, and some forms can be drug induced. It is triggered in cats by eating onions[13] or acetaminophen (paracetamol). It can be triggered in dogs by ingesting onions or zinc, and in horses by ingesting dry red maple leaves.

[edit] Hyperanemia
Hyperanemia is a severe form of anemia, in which the hematocrit is below 10%.

[edit] Refractory anemia

Refractory anemia is an anemia which does not respond to treatment.[14] It is often seen secondary to myelodysplastic syndromes.[15] Iron deficiency anemia may also be refractory as a clinical manifestation of gastrointestinal problems which disrupt iron metabolism. [16]

[edit] Grading of anemia

WHO Grading of anemia:[17][18]

Grade 1 (Mild Anemia): 10 g/dl - cutoff point for ages Grade 2 (Moderate Anemia): 7-10 g/dl Grade 3 (Severe Anemia): below 7 g/dl

National Cancer Institute Grading of Anemia:[19]

Grade 0 (within normal limits) 12.016.0 g/dl for women and 14.018.0 g/ dl for men Grade 1 (Mild) 10 g/dl to levels within normal limits Grade 2 (Moderate) 8.010.0 g/dl Grade 3 (Severe) 6.57.9 g/dl Grade 4 (Life threatening) <6.5 g/dl

[edit] Causes
Broadly, causes of anemia may be classified as impaired red blood cell (RBC) production, increased RBC destruction (hemolytic anemias), blood loss and fluid overload (hypervolemia). Several of these may interplay to cause anemia eventually. Indeed, the most common cause of anemia is blood loss, but this usually doesn't cause any lasting symptoms unless a relatively impaired RBC production develops, in turn most commonly by iron deficiency.[20] (See Iron deficiency anemia)

[edit] Impaired production

Disturbance of proliferation and differentiation of stem cells. [21] o Pure red cell aplasia [21] o Aplastic anemia, affecting all kinds of blood cells. Fanconi anemia is a hereditary disorder or defect featuring aplastic anemia and various other abnormalities. [21] o Anemia of renal failure, by insufficient erythropoietin production o Anemia of endocrine disorders Disturbance of proliferation and maturation of erythroblasts [21] o Pernicious anemia is a form of megaloblastic anemia due to vitamin B12 deficiency dependent on impaired absorption of vitamin B12. [21] o Anemia of folic acid deficiency. As with vitamin B12, it causes megaloblastic anemia o Anemia of prematurity, by diminished erythropoietin response to declining hematocrit levels, combined with blood loss from laboratory testing. It generally occurs in premature infants at 2 to 6 weeks of age. [21] o Iron deficiency anemia, resulting in deficient heme synthesis [21] o thalassemias, causing deficient globin synthesis o Congenital dyserythropoietic anemias, causing ineffective erythropoiesis [21] o Anemia of renal failure (also causing stem cell dysfunction) Other mechanisms of impaired RBC production [21] o Myelophthisic anemia or myelophthisis is a severe type of anemia resulting from the replacement of bone marrow by other materials, such as malignant tumors or granulomas. [21] o Myelodysplastic syndrome [21] o anemia of chronic inflammation

[edit] Increased destruction

Further information: Hemolytic anemia Anemias of increased red blood cell destruction are generally classified as hemolytic anemias. These are generally featuring jaundice and elevated LDH levels.

Intrinsic (intracorpuscular) abnormalities,[21] where there the red blood cells have defects that cause premature destruction. All of these, except paroxysmal nocturnal hemoglobinuria, are hereditary genetic disorders.[22] [21] o Hereditary spherocytosis is a hereditary defect that results in defects in the RBC cell membrane, causing the erythrocytes to be sequestered and destroyed by the spleen. [21] o Hereditary elliptocytosis, another defect in membrane skeleton proteins [21] o Abetalipoproteinemia, causing defects in membrane lipids o Enzyme deficiencies [21] Pyruvate kinase and hexokinase deficiencies, causing defect glycolysis Glucose-6-phosphate dehydrogenase deficiency and glutathione synthetase deficiency,[21] causing increased oxidative stress o Hemoglobinopathies [21] Sickle cell anemia [21] Hemoglobinopathies causing unstable hemoglobins [21] o Paroxysmal nocturnal hemoglobinuria Extrinsic (extracorpuscular) abnormalities o Antibody-mediated Warm autoimmune hemolytic anemia is an anemia caused by autoimmune attack against red blood cells, primarily by IgG. It is the most common of the autoimmune hemolytic diseases.[23] It can be idiopathic, that is, without any known cause, drug-associated or secondary to another disease such as systemic lupus erythematosus, or a malignancy, such as chronic lymphocytic leukemia (CLL)[24][24] Cold agglutinin hemolytic anemia is primarily mediated by IgM. It can be idiopathic[25] or result from an underlying condition. [21] Rh disease, one of the causes of hemolytic disease of the newborn [21] Transfusion reaction to blood transfusions o Mechanical trauma to red cells Microangiopathic hemolytic anemias, including thrombotic thrombocytopenic purpura and disseminated intravascular coagulation[21] [21] Infections, including malaria heart surgery

[edit] Blood loss

Anemia of prematurity from frequent blood sampling for laboratory testing, combined with insufficient RBC production.

Trauma[21] or surgery, causing acute blood loss Gastrointestinal tract lesions,[21] causing a rather chronic blood loss Gynecologic disturbances,[21] also generally causing chronic blood loss From menstruation, mostly among young women

[edit] Fluid overload

Fluid overload (hypervolemia) causes decreased hemoglobin concentration and apparent anemia:

General causes of hypervolemia include excessive sodium or fluid intake, sodium or water retention and fluid shift into the intravascular space.[26] Anemia of pregnancy is anemia that is induced by blood volume expansion experienced in pregnancy.

[edit] Treatments
Treatments for anemia depend on severity and cause. Iron deficiency from nutritional causes is rare in men and post-menopausal women. The diagnosis of iron deficiency mandates a search for potential sources of loss such as gastrointestinal bleeding from ulcers or colon cancer. Mild to moderate iron-deficiency anemia is treated by oral iron supplementation with ferrous sulfate, ferrous fumarate, or ferrous gluconate. When taking iron supplements, it is very common to experience stomach upset and/or darkening of the feces. The stomach upset can be alleviated by taking the iron with food; however, this decreases the amount of iron absorbed. Vitamin C aids in the body's ability to absorb iron, so taking oral iron supplements with orange juice is of benefit. Vitamin supplements given orally (folic acid) or intramuscularly (vitamin B-12) will replace specific deficiencies. In anemia of chronic disease, anemia associated with chemotherapy, or anemia associated with renal disease, some clinicians prescribe recombinant erythropoietin, epoetin alfa, to stimulate red-cell production. In severe cases of anemia, or with ongoing blood loss, a blood transfusion may be necessary.

[edit] Blood transfusions

Doctors attempt to avoid blood transfusion in general, since multiple lines of evidence point to increased adverse patient clinical outcomes with more intensive transfusion strategies. The physiological principle that reduction of oxygen delivery associated with anemia leads to adverse clinical outcomes is balanced by the finding that transfusion does not necessarily mitigate these adverse clinical outcomes.

In severe, acute bleeding, transfusions of donated blood are often lifesaving. Improvements in battlefield casualty survival is attributable, at least in part, to the recent improvements in blood banking and transfusion techniques.[citation needed] Transfusion of the stable but anemic hospitalized patient has been the subject of numerous clinical trials. Four randomized controlled clinical trials have been conducted to evaluate aggressive versus conservative transfusion strategies in critically ill patients. All four of these studies failed to find a benefit with more aggressive transfusion strategies.[27][28][29][30] In addition, at least two retrospective studies have shown increases in adverse clinical outcomes in critically ill patients that underwent more aggressive transfusion strategies.[31][32]

[edit] Hyperbaric oxygen

Treatment of exceptional blood loss (anemia) is recognized as an indication for hyperbaric oxygen (HBO) by the Undersea and Hyperbaric Medical Society.[33][34] The use of HBO is indicated when oxygen delivery to tissue is not sufficient in patients who cannot be transfused for medical or religious reasons. HBO may be used for medical reasons when threat of blood product incompatibility or concern for transmissible disease are factors.[33] The beliefs of some religions (ex: Jehovah's Witnesses) may require they use the HBO method.[33] In 2002, Van Meter reviewed the publications surrounding the use of HBO in severe anemia and found that all publications report a positive result.[35] INTRODUCTION The inside of the uterus has two layers. The thin inner layer is called the endometrium. The thick outer layer is the myometrium (myo = muscle) (figure 1). In women who menstruate, the endometrium thickens every month in preparation for pregnancy. If the woman does not become pregnant, the endometrial lining is shed during the menstrual period. After menopause, the lining normally stops growing and shedding. Under normal circumstances, a woman's uterus sheds a limited amount of blood during each menstrual period (less than 5 tablespoons or 80 mL). Bleeding that occurs between menstrual periods or excessive menstrual bleeding is considered to be abnormal uterine bleeding. Once a woman who is not taking hormone therapy enters menopause and the menstrual cycles have ended, any uterine bleeding is considered abnormal. Abnormal uterine bleeding can be caused by many different conditions. This topic review discusses the possible causes of abnormal bleeding, how it is evaluated, and various treatment strategies that may be recommended. CAUSES OF ABNORMAL UTERINE BLEEDING

Most conditions that cause abnormal uterine bleeding can occur at any age, but some are more likely to occur at a particular time in a woman's life. Abnormal uterine bleeding in young girls Bleeding before menarche (the first period in a girl's life) is always abnormal. It may be caused by trauma, a foreign body (such as toys, coins, or toilet tissue), irritation of the genital area (due to bubble bath, soaps, lotions, or infection), or urinary tract problems. Bleeding can also occur as a result of sexual abuse. Adolescents Many girls have episodes of irregular bleeding during the first few months after their first menstrual period. This usually resolves without treatment when the girl's hormonal cycle and ovulation normalizes. If bleeding persists beyond this time, or if the bleeding is heavy, further evaluation is needed. Abnormal bleeding in this age group can also be caused by any of the conditions that cause bleeding in all premenopausal women, including: pregnancy, infection, and bleeding disorder or other medical illnesses. These and other causes are discussed in the next section. Premenopausal women Many different conditions can cause abnormal bleeding in women between adolescence and menopause. Abrupt changes in hormone levels at the time of ovulation can cause vaginal spotting, or small amounts of bleeding. Breakthrough bleeding can also occur in premenopausal women who use hormonal birth control methods. Some women do not ovulate regularly, causing irregular hormone levels and intermittent light or heavy bleeding. Although anovulation is most common when periods first begin and during perimenopause, it can occur at any time during the reproductive years. (See "Patient information: Absent or irregular periods".) Some women who ovulate normally experience excessive blood loss during their periods or bleed between periods. The most common causes of such bleeding are uterine fibroids or polyps. These irregular growths and benign tumors are composed of uterine tissue that distort the structure of the uterus and lead to abnormal uterine bleeding. Fibroids and polyps can also occur in anovulatory women. (See "Patient information: Uterine fibroids" and "Patient information: Menorrhagia (excessive menstrual bleeding)".) Other causes of abnormal uterine bleeding in premenopausal women include:

Pregnancy Cancer or precancer of the cervix or the endometrium (lining of the uterus) (see "Patient information: Endometrial cancer diagnosis and staging") Infection or inflammation of the cervix or endometrium Clotting disorders such as von Willebrand disease, platelet abnormalities, or problems with clotting factors Medical illnesses such as hypothyroidism, liver disease, or chronic renal disease

Birth control pills Girls and women who use hormonal birth control (eg, pills, shot, patch) may experience "breakthrough" bleeding between periods. If this occurs during the first few

months, it may be due to changes in the lining of the uterus. If it persists for more than a few months, evaluation may be needed and/or a different birth control pill may be recommended. (See "Patient information: Hormonal methods of birth control".) Breakthrough bleeding can also happen if birth control is forgotten or taken late. In this situation, there is a risk that the woman could become pregnant if she has sex. Another form of birth control (eg, condoms) is recommended if the pill/patch/shot is not taken on time. Women in the menopausal transition Before the menstrual periods end, a woman passes through a period called the menopausal transition. During the menopausal transition, normal hormonal cycling begins to change and ovulation may be inconsistent. While estrogen secretion continues, progesterone secretion declines. These hormonal changes can cause the endometrium to grow and produce excess tissue, increasing the chances that polyps or endometrial hyperplasia (thickened lining of the uterus) will develop and potentially cause abnormal bleeding. Women in the menopausal transition are also at risk for other conditions that cause abnormal bleeding, including cancer, infection, and bodywide illnesses. Further evaluation is needed in women with persistent irregular menstrual cycles or an episode of profuse bleeding. Women in the menopausal transition still ovulate some of the time and can become pregnant; pregnancy can cause abnormal bleeding. In addition, women in perimenopause may use hormonal birth control medications, which can cause breakthrough bleeding. Menopausal women A number of conditions can cause abnormal bleeding during the menopause. Women who take hormone replacement therapy may experience cyclical bleeding. Any other bleeding that occurs during menopause is abnormal and should be investigated. Causes of abnormal bleeding during menopause include:

Atrophy (excessive thinning) of the tissue lining the vagina and uterus Cancer of the uterine lining (endometrium) (see "Patient information: Endometrial cancer diagnosis and staging") Polyps or fibroids Endometrial hyperplasia Infection of the uterus Use of blood thinners or anticoagulants Side effects of radiation therapy

ABNORMAL UTERINE BLEEDING EVALUATION Initial assessment While taking a woman's medical history, a clinician will review the duration and amount of bleeding; factors that seem to bring the bleeding on; symptoms that occur along with the bleeding such as pain, fever, or vaginal odor; if bleeding occurs after sexual intercourse; whether there is a personal or family history of bleeding disorders; the woman's medical history and medications she is taking; recent weight changes, stress, a new exercise program, or underlying medical problems.

The clinician will perform a physical examination to evaluate the woman's overall health, and a pelvic examination to confirm that the bleeding is from the uterus and not from another site (eg, the external genitals or rectum). During the pelvic exam, the clinician will look for any obvious lesions (cuts, sores, or tumors) and will examine the size and shape of the uterus. He or she will examine the cervix to look for signs of cervical bleeding, and a Pap smear may be obtained to examine the cells of the cervix (the lower end of the uterus, where it opens to the vagina). (See "Patient information: Cervical cancer screening".) Lab tests In premenopausal women, a pregnancy test is performed. If there is any abnormal vaginal discharge, a cervical culture may be performed. Blood tests may also be done to determine if there are problems with blood clotting or other bodywide conditions, such as thyroid disease, liver disease, or kidney problems. Tests to determine ovulatory status Because hormonal irregularities can contribute to abnormal uterine bleeding, testing may be recommended to determine if the woman ovulates (produce an egg) during each monthly cycle. Endometrial assessment Tests that assess the endometrium (lining of the uterus) may be performed to rule out endometrial cancer and structural abnormalities such as uterine fibroids or polyps. Such tests include: Endometrial biopsy An endometrial biopsy is often performed in women over age 35 to rule out endometrial cancer or abnormal endometrial growths. A biopsy may also be performed in women younger than 35 if they have risk factors for endometrial cancer. Risks include obesity, chronic anovulation, history of breast cancer, tamoxifen use or a family history of breast cancer or colon cancer. (See "Patient information: Endometrial cancer diagnosis and staging".) During the biopsy, a thin instrument is inserted through the vagina into the uterus to obtain a small sample of endometrial tissue. The biopsy can be performed in a healthcare provider's office without anesthesia. Because only a small portion of the endometrium is sampled, the biopsy may miss some causes of bleeding and other tests are sometimes necessary. Transvaginal ultrasound An ultrasound uses sound waves to measure an organ's shape and structure. In a transvaginal ultrasound, a small ultrasound probe is inserted into the vagina so that it is closer to the uterus and can provide a clear image of the uterus. The lining of the uterus is evaluated and measured; postmenopausal women normally have a very thin endometrial lining (usually less than 4 or 5 mm). Ultrasound cannot distinguish between different types of abnormalities (eg, polyp versus cancer) and further testing may be necessary. Saline infusion sonography ( sonohysterography) In this test, a transvaginal ultrasound is performed after sterile saline is instilled into the uterus. This procedure gives a better picture of the inside of the uterus, and small lesions can be more easily detected. However, because tissue samples cannot be obtained during the procedure, a final diagnosis is not always possible and additional evaluation, usually including hysteroscopy with dilation and curettage (D&C) may be necessary.

Imaging tests A magnetic resonance image (MRI) is a non-invasive test that is sometimes used to determine if fibroids or other structural abnormalities of the uterus are present. Hysteroscopy During hysteroscopy, a small scope is inserted through the cervix and into the uterus. Air or fluid is injected to expand the uterus and to allow the physician to see the inside of the uterus. Tissue samples may be taken. Anesthesia is used to minimize discomfort during the procedure. In most cases, hysteroscopy is performed along with a D&C. Dilation and curettage (D&C) In a D&C, the cervix or opening of the uterus is dilated and instruments are inserted and used to remove endometrial or uterine tissue. A D&C usually requires anesthesia. It can sometimes be used as a treatment for prolonged or excessive bleeding that is due to hormonal changes and that is unresponsive to other treatments. (See "Patient information: Dilation and curettage (D and C)".) ABNORMAL UTERINE BLEEDING TREATMENT The treatment of abnormal bleeding is based upon the underlying cause. Birth control pills Birth control pills are often used to treat uterine bleeding that is due to hormonal changes or hormonal irregularities. Birth control pills may be used in women who do not ovulate regularly to establish regular bleeding cycles and prevent excessive growth of the endometrium. In women who do ovulate, they may be used to treat excessive menstrual bleeding. Nonsteroidal anti-inflammatory drugs (NSAIDS, eg ibuprofen, naproxen sodium) may also be helpful in reducing blood loss and cramping in these women. During the menopausal transition, birth control pills or other hormonal therapy may be used to regulate the menstrual cycle and prevent excessive growth of the endometrium. (See "Patient information: Menorrhagia (excessive menstrual bleeding)".) Progesterone Progesterone is a hormone made by the ovary that is effective in preventing excessive bleeding in women who do not ovulate regularly. A synthetic form of progesterone, called progestin, may be recommended to treat abnormal bleeding. Progestins are usually given as pills (eg, medroxyprogesterone acetate, norethindrone), and are taken once a day for 10 to 12 days each month or two. Progestins can be taken for longer periods if there has been overgrowth of the uterine lining. Vaginal bleeding will begin before the seventh day of progestin treatment if the uterine lining is overgrown; otherwise, it may not be seen until several days after the last progestin tablet is taken. In some cases, the progestin is given on a regular basis (eg, every few months) to prevent excessive growth of the uterine lining and heavy menstrual bleeding. If no bleeding is seen after progestin treatment, the possibility of an unintended pregnancy should be explored. Progestins may also be given in other ways, such as in an injection, an implant, or an intrauterine device. These treatments are discussed in detail in a separate topic review. (See "Patient information: Menorrhagia (excessive menstrual bleeding)".)

Intrauterine device An intrauterine contraceptive device (IUD) that secretes progestin (eg, Mirena) may be recommended for women who do not ovulate regularly. IUDs are inserted by a healthcare provider through the vagina and cervix into the uterus. Most are made of molded plastic and include an attached plastic string that projects through the cervix, enabling the woman to check that the device remains in place (picture 1). Progestin-releasing IUDs decrease menstrual blood loss by 40 to 50 percent and decrease pain associated with periods. Some women completely stop having menstrual bleeding as a result of the IUD, which is reversible when the IUD is removed. (See "Patient information: Long-term methods of birth control".) Surgery Surgery may be necessary to remove abnormal uterine structures (eg, fibroids, polyps). Women who have completed childbearing and have heavy menstrual bleeding can consider a surgical procedure such as endometrial ablation. This procedure is done while the woman is under general or regional anesthesia, and uses heat, cold, or a laser to destroy the lining of the uterus. More information about endometrial ablation is available in a separate topic review. (See "Patient information: Menorrhagia (excessive menstrual bleeding)".) Women with fibroids can have surgical treatment of their fibroids, either by removing the fibroid(s) (eg, myomectomy) or by reducing the blood supply of the fibroids (eg, uterine artery embolization). More information about these treatments is available separately. (See "Patient information: Uterine fibroids".)